A majority of pancreatic cancer (PC) patients (> 80%) present with an unresectable primary tumor with distant metastasis at the time of diagnosis due to its asymptomatic nature and lack of methods for early detection. While the overall 5-year survival rate of PC is dismal, signi?cantly better outcomes have been reported for early stage smaller tumors. PC is believed to progress through a series of histological changes and recent estimates indicate that these changes require 15-20 years to develop into invasive metastatic disease, hence providing a window of opportunity to intervene. While early diagnosis is an obvious strategy to improve the survival of PC patients, lack of non-invasive biomarkers for risk prediction of precursor lesions or early stage invasive disease impedes our ability to diagnose PC during this window. Premalignant cystic lesions of the pancreas offer unique opportunity for early diagnosis. To meet the EDRN stated goal of performing a validation study for early cancer detection and risk assessment likely to yield meaningful results within 5 years, we propose an innovative approach that could lead to the development of a clinically useful biomarker in this time frame. Additionally, we propose to study cystic neoplasms since IPMN and MCN offer a unique opportunity to identify pancreatic premalignant lesions and serve as a target for early detection strategies. The candidate biomarkers studies in our application have been identified and evaluated over the past 5 years in EDRN-funded biomarker developmental laboratories (BDLs). Studies from the laboratories of participating investigators have conclusively established that mucin overexpression is a hallmark of pancreatic cancer and have identified biomarkers (MUC5AC and its 2 glycoforms, MUC4 and a glycoform of endorepellin) that can effectively distinguish a) patients with resectable PC patients from patients with benign pancreatic diseases; b) mucinous and non- mucinous cysts; c) high-grade from moderate- and low-grade mucinous cysts and d). high-risk intestinal type IPMNs and low risk gastric type IPMNs. The overall objective of this CVC proposal is to demonstrate the ability of the aforementioned biomarkers to distinguish pancreatic adenocarcinoma (PC) patients from healthy controls, patients with benign biliary obstruction and chronic pancreatitis (CP), and to identify those cysts with high malignant potential. We have a large number of high quality, well-characterized specimens from patients with pancreatic disease and diseased controls that were collected and processed following protocols developed through the EDRN. Two specific aims are proposed. Aim 1 will use available samples from our biospecimen repository to evaluate MUC5AC and MUC4 as biomarkers to distinguish pancreatic adenocarcinoma (PC) patients from healthy controls, and from patients with benign biliary obstruction and chronic pancreatitis (CP). Aim 2 will determine if our biomarkers can identify those cysts with high lethal potential from those with a low risk for malignant transformation.